tbuckley/cabot-search huggingface dataset:
Lessons learned from phase 3 trials of immunotherapy for glioblastoma: Time for longitudinal sampling?
Authors: Ethan Chen, Alexander L Ling, David A Reardon, E Antonio Chiocca
Journal: Neuro-Oncology (2023)

Abstract Glioblastoma (GBM)’s median overall survival is almost 21 months. Six phase 3 immunotherapy clinical trials have recently been published, yet 5/6 did not meet approval by regulatory bodies. For the sixth, approval is uncertain. Trial failures result from multiple factors, ranging from intrinsic tumor biology to clinical trial design. Understanding the clinical and basic science of these 6 trials is compelled by other immunotherapies reaching the point of advanced phase 3 clinical trial testing. We need to understand more of the science in human GBMs in early trials: the “window of opportunity” design may not be best to understand complex changes brought about by immunotherapeutic perturbations of the GBM microenvironment. The convergence of increased safety of image-guided biopsies with “multi-omics” of small cell numbers now permits longitudinal sampling of tumor and biofluids to dissect the complex temporal changes in the GBM microenvironment as a function of the immunotherapy.
Progress in cancer neuroscience
Authors: Yu‐Long Lan, Shuang Zou, Wen Wang, Qi Chen, Yongjian Zhu
Journal: MedComm (2023)

Abstract Cancer of the central nervous system (CNS) can crosstalk systemically and locally in the tumor microenvironment and has become a topic of attention for tumor initiation and advancement. Recently studied neuronal and cancer interaction fundamentally altered the knowledge about glioma and metastases, indicating how cancers invade complex neuronal networks. This review systematically discussed the interactions between neurons and cancers and elucidates new therapeutic avenues. We have overviewed the current understanding of direct or indirect communications of neuronal cells with cancer and the mechanisms associated with cancer invasion. Besides, tumor‐associated neuronal dysfunction and the influence of cancer therapies on the CNS are highlighted. Furthermore, interactions between peripheral nervous system and various cancers have also been discussed separately. Intriguingly and importantly, it cannot be ignored that exosomes could mediate the “wireless communications” between nervous system and cancer. Finally, promising future strategies targeting neuronal–brain tumor interactions were reviewed. A great deal of work remains to be done to elucidate the neuroscience of cancer, and future more research should be directed toward clarifying the precise mechanisms of cancer neuroscience, which hold enormous promise to improve outcomes for a wide range of malignancies.
Long‐term complete remission and peripheral biomarkers in Hodgkin lymphoma patients after decitabine‐plus‐camrelizumab epi‐immunotherapy and treatment cessation
Authors: Chunmeng Wang, Yuting Pan, Yang Liu, Bing Guo, Jinhong Shi, Guanghua Rong, Zhipeng Guo, Zhifang Li, Qingming Yang, Jing Nie, Weidong Han
Journal: MedComm (2023)

Patients with relapsed/refractory classical Hodgkin lymphoma (cHL) achieve complete response (CR) after decitabine-plus-camrelizumab therapy, while long-term outcome especially after treatment discontinuation remains unclear. We present a retrospective analysis of 87 relapsed/refractory cHL patients who acquired CR after decitabine-plus-camrelizumab. Patients were divided into two groups and received consolidation treatment every 3-4 or 6-12 weeks, and 1-year of continuous CR was guaranteed for treatment cessation. At a median follow-up of 5.3 years, the median relapse-free survival (RFS) after achieving CR with decitabine-plus-camrelizumab therapy was 4.5 years, and patients underwent consolidation per 3-4 weeks might have longer RFS. The baseline percentage of peripheral central memory T cells was not associated with RFS, while patients with higher pretreatment serum levels of interleukin-6 (IL-6) and lactate dehydrogenase (LDH) had significantly shorter RFS and increased risk for disease recurrence. Fifty-seven patients completed and discontinued decitabine-plus-camrelizumab, and their median RFS had not been reached. The 2-year RFS rate after treatment cessation was 78% (95% CI, 67-90%). Patients in the high-risk subgroup with higher pretreatment IL-6 and LDH levels showed poor treatment-free remission. Moreover, decitabine-plus-camrelizumab therapy was safe and cost-effective. In conclusion, patients who obtained CR with decitabine-plus-camrelizumab and received consolidation per 3-4 weeks can achieve long-term remission after treatment discontinuation.
Impact of urinary diversion type on urethral recurrence following radical cystectomy for bladder cancer: propensity score matched and weighted analyses of retrospective cohort
Authors: Jiwoong Yu, Chung Un Lee, Jae Hoon Chung, Wan Song, Minyong Kang, Hwang Gyun Jeon, Byong Chang Jeong, Seong Il Seo, Seong Soo Jeon, Hyun Hwan Sung
Journal: International Journal of Surgery (2023)

Background: The absence of randomized controlled trials and the presence of inherent selection bias in existing studies have led to ongoing uncertainty regarding the impact of urinary diversion (UD) type (orthotopic UD or nonorthotopic UD) on urethral recurrence (UR) following radical cystectomy (RC) for bladder cancer. This study aimed to assess the impact of the UD types on UR after RC and to identify predictive factors associated with UR. Materials and methods: This retrospective analysis encompassed 612 male patients who underwent RC for urothelial carcinoma of the bladder. Among them, 341 patients received nonorthotopic UD [ileal conduit (IC) or ureterocutaneostomy (UC)], whereas 271 received orthotopic neobladder (NB) between January 2012 and October 2022. To mitigate potential biases, we employed 1:1 propensity score matching (PSM) and stabilized inverse probability treatment weighting (IPTW). Kaplan–Meier analysis and log-rank tests were employed to assess UR-free survival between the IC/UC and NB groups, while multivariable Cox regression analysis was conducted to determine predictive factors for UR. Results: Among the 612 patients included, 33 (5.4%) experienced UR. PSM yielded matched cohort comprising 412 patients, evenly distributed with 206 patients in each group (IC/UC and NB). Clinicopathological data demonstrated similarity between the two groups. Patients who underwent NB exhibited significantly superior UR-free survival in both PSM (log-rank P =0.033) and IPTW cohorts (log-rank P =0.009). NB reconstruction (vs. IC/UC) emerged as a substantial protective factor against UR [hazard ratio (HR) 0.283; 95% CI: 0.088–0.916; P =0.035], whereas prostatic urethral involvement was identified as a significant risk factor (HR 5.328; 95% CI: 1.298–21.868; P =0.020) in the PSM cohort. Additionally, in the IPTW cohort, NB reconstruction (vs. IC/UC) maintained its significance as a protective factor against UR (HR 0.336; 95% CI: 0.131–0.858; P =0.023) along with neoadjuvant chemotherapy (HR 0.335; 95% CI: 0.116–0.969; P =0.044), whereas prostatic urethral involvement remained a significant risk factor (HR 3.752; 95% CI: 1.484–9.488; P =0.005). Conclusions: Even after mitigating selection bias, NB reconstruction holds a protective effect against UR in male patients undergoing RC for bladder cancer.
Letter to the editor: Long-term survival after female pelvic organ-sparing radical cystectomy versus standard radical cystectomy: a multi-institutional propensity score-matched analysis
Authors: Yingjie Chen, Yanling Liao, Yuwei Yang, Xiaochun Zheng
Journal: International Journal of Surgery (2023)

Chen, Yingjie PhD; Liao, Yanling PhD; Yang, Yuwei MS; Zheng, Xiaochun PhD Author Information
Comparative dose-response study on the infusion of norepinephrine combined with intravenous ondansetron versus placebo for preventing hypotension during spinal anesthesia for cesarean section: a randomised controlled trial
Authors: Zhi-min Sheng, Heng-qiu Sun, Jun-qin Mao, Jie Liu, Gang Liang, Zhong Mei
Journal: International Journal of Surgery (2023)

Background: Ondansetron has been reported to attenuate the incidence of spinal anaesthesia-induced hypotension (SAIH) and norepinephrine requirement during caesarean section. However, no quantitative study has evaluated the extent of this effect. This study aimed to determine the dose-response of prophylactic infusion of norepinephrine to prevent SAIH in parturients who received intravenous ondansetron or placebo before spinal anaesthesia for caesarean section. The median effective dose (ED 50 ) and 90% effective dose (ED 90 ) were compared to evaluate the effect of ondansetron versus placebo on the norepinephrine requirement. Materials and methods: One hundred fifty parturients undergoing caesarean section were randomized to receive either 0.1 mg/kg ondansetron (group O) or saline control (group C) 10 min before spinal anaesthesia. The parturients were randomly assigned to one of five different norepinephrine infusion groups: 0.02, 0.04, 0.06, 0.08 or 0.10 µg/kg/min. An effective infusion dose of norepinephrine was defined as non-occurrence of hypotension during the study period. The values for ED 50 and ED 90 of norepinephrine infusion were determined using probit regression. Differences between the two groups were evaluated by comparing the relative median potency with 95% CIs. Results: The ED 50 values were 0.033 (95% CIs, 0.024–0.043) µg/kg/min in group C and 0.021 (95% CIs, 0.013–0.029) µg/kg/min in group O. The ED 90 values were 0.091 (95% CIs 0.068–0.147) µg/kg/min in group C and 0.059 (95% CIs 0.044–0.089) µg/kg/min in group O, respectively. The estimate of the relative median potency for norepinephrine in group C versus group O was 0.643 (95% CIs, 0.363–0.956). The incidence of side effects was comparable between groups. No significant difference in neonatal outcomes. Conclusion: Intravenous ondansetron 0.1 mg/kg before spinal anaesthesia significantly reduced the dose requirement of prophylactic norepinephrine infusion in parturients undergoing elective caesarean section. This finding is potentially useful for clinical practice and further research.
A commentary on ‘Can prophylactic tamsulosin reduce the risk of urinary retention after surgery? A systematic review and meta-analysis of randomized control trials’ (Int J Surg 2023 Mar 1;109(3):438–448)
Authors: Hongjin Shi, Caifang Guo, Huake Wang, Shi Fu, Haifeng Wang
Journal: International Journal of Surgery (2023)

aDepartment of Urology, The Second Affiliated Hospital of Kunming Medical University, Yunnan, 650106, China bDepartment of Urology, Kunming Children's Hospital, Yunnan, 650106, China Study design:Commentary Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article. Published online ■ ■ *Corresponding Author. Address: Kunming Medical University Second Affliated Hospital CHINA. E-mail address: [email protected] (H. Wang). This is an open access article distributed under the Creative Commons Attribution-NoDerivatives License 4.0, which allows for redistribution, commercial and non-commercial, as long as it is passed along unchanged and in whole, with credit to the author. http://creativecommons.org/licenses/by-nd/4.0/
Normalization weighted combination scores re-evaluate TNM staging of gastric cancer: a retrospective cohort study based on a multicenter database
Authors: Junpeng Wu, Hao Wang, Xin Yin, Yufei Wang, Zhanfei Lu, Jiaqi Zhang, Yao Zhang, Yingwei Xue
Journal: International Journal of Surgery (2023)

Background: The pathological depth of tumor invasion (pT) and lymph node metastasis (pN) are critical independent prognostic factors for patients with gastric cancer, representing effective methods for evaluating prognosis. In this study, we employed a normalization weight combination score to calculate the weight ratio of the pT stage and pN stage. Subsequently, we established a novel wTN staging model based on these T and N weights, evaluating its prognostic capacity. Methods: This study utilized a training cohort from A Medical University Cancer Hospital and a validation cohort from the SEER database. LASSO and Cox regression were employed to screen clinical characteristics. Multivariate linear regression and cluster analysis calculated the weight ratio of T stage and N stage in the training and validation cohorts, respectively, followed by re-staging. Prognostic value was evaluated using C-index, likelihood ratio, Wald, and Score tests for wTN stage and TNM stage. A nomogram model was developed, and accuracy was assessed using ROC, DCA, and RCS analyses. Results: LASSO was used for initial screening, selecting 8 potential features for Cox analysis. Age, tumor size, MLNs, and tumor location were confirmed as independent prognostic factors. wTN was calculated in the training and validation cohorts, and nomograms were established with the independent factors. N stage had a higher weight proportion than T stage in both cohorts (0.625/0.375 in training cohort, 0.556/0.444 in validation cohort). wTN outperformed the 8 th TNM stage in C-index, likelihood ratio, Wald, and Score tests in the training cohort, with successful validation in the validation cohort. Stratified analysis of distinct pathological types further demonstrates that wTN staging exhibits superior prognostic performance. Conclusion: The wTN staging model based on T stage and N stage weights has a good prognostic value for gastric cancer patients. The same conclusion was obtained in different pathological stratification.
When I use a word . . . Medicines regulation—poisons
Authors: Jeffrey K Aronson
Journal: BMJ (2023)

In his famous dictum, the 16th century physician and alchemist Paracelsus declared that “Alle ding sind gifft und nichts ohn gifft,” “Everything is a poison and nothing is not a poison,” by which he implied that it was always possible to have too much of a good thing. Today, in contrast, we typically regard poisons as substances that can cause harm in small quantities. However, the 1868 Pharmacy Act, “An Act to regulate the Sale of Poisons, and alter and amend the Pharmacy Act 1852,” took more of a Paracelsian approach, including as it did in its schedule, its list of proscribed poisons, both opiates and chloroform, constituents, along with prussic acid, of formulations known as chlorodynes, which had caused many cases of poisoning. The aim of the act was not merely to protect the public but also to afford a new breed of chemists and druggists and pharmaceutical chemists the right to a monopoly on the dispensing of medicines, while at the same time protecting others, such as legally qualified apothecaries and members of the Royal College of Veterinary Surgeons, who also had the right to retail and dispense poisons.
Benefit of perioperative radiotherapy for hepatocellular carcinoma: a quality-based systematic review and meta-analysis
Authors: Chai Hong Rim, Sunmin Park, Won Sup Yoon
Journal: International Journal of Surgery (2023)

Introduction: Although surgery is the standard curative modality for hepatocellular carcinoma, more than two-thirds experience intrahepatic recurrence. Since no standard perioperative treatment has been established, the authors performed a meta-analysis to evaluate the benefits of perioperative radiotherapy (RT). Methods: The PubMed, MEDLINE, EMBASE, and Cochrane Library were searched until May 2023. Randomized or propensity-matched studies evaluating at least five major clinical factors investigating benefit of perioperative RT, were included. The main effect measure were the pooled odds ratios (OR) regarding the benefit of perioperative RT using 2-year overall survival (OS) and 1-year disease-free survival (DFS) data. Results: Seven studies (five randomized and two propensity-matched studies) involving 815 patients were included. The pooled ORs for 1-year DFS and 2-year OS were 0.359 (95% CI: 0.246–0.523) and 0.371 (95% CI: 0.293–0.576), respectively, favoring perioperative RT, with very low heterogeneity. In the subgroup analyses, the benefits of OS and DFS were consistent between the two subgroups [portal vein thrombosis (PVT) and narrow resection margin (RM) groups]. In the PVT subgroup, the pooled OS rates at both 1-year and 2-year (75.6 vs. 36.9%, P &lt;0.001; 25.6 vs. 9.9%, P =0.004) and DFS rates at both 1-year and 2-year (25.2 vs. 10.3%, P =0.194; 11.9 vs. 3.0%, P =0.022) were higher in the perioperative RT group. In the narrow RM subgroup, the surgery and RT groups showed higher pooled OS rates for both 1-year and 2-year (97.3 vs. 91.9%, P =0.042; 90.4 vs. 78.7%, P =0.051) and DFS (88.1 vs. 72.6%, P &lt;0.001; 70.1 vs. 51.7%, P &lt;0.001). Grade 5 toxicity was not reported, and three studies reported grade ≥3 or higher liver function test abnormalities, ranging from 4.8–19.2%. Conclusion: The present study supports the oncological benefits of perioperative RT, for cases with high-risk of recurrence. Oncologic outcomes between subgroups differed according to clinical indications.
Myeloid OTULIN deficiency couples RIPK3-dependent cell death to Nlrp3 inflammasome activation and IL-1β secretion
Authors: M. Giulia Doglio, Lien Verboom, Emily Ruilova Sosoranga, Ulrika C. Frising, Tomoko Asaoka, Yannick Gansemans, Filip Van Nieuwerburgh, Geert van Loo, Andy Wullaert
Journal: Science Immunology (2023)

Loss-of-function mutations in the deubiquitinase OTULIN result in an inflammatory pathology termed “OTULIN-related autoinflammatory syndrome” (ORAS). Genetic mouse models revealed essential roles for OTULIN in inflammatory and cell death signaling, but the mechanisms by which OTULIN deficiency connects cell death to inflammation remain unclear. Here, we identify OTULIN deficiency as a cellular condition that licenses RIPK3-mediated cell death in murine macrophages, leading to Nlrp3 inflammasome activation and subsequent IL-1β secretion. OTULIN deficiency uncoupled Nlrp3 inflammasome activation from gasdermin D–mediated pyroptosis, instead allowing RIPK3-dependent cell death to act as an Nlrp3 inflammasome activator and mechanism for IL-1β release. Accordingly, elevated serum IL-1β levels in myeloid-specific OTULIN-deficient mice were diminished by deleting either Ripk3 or Nlrp3 . These findings identify OTULIN as an inhibitor of RIPK3-mediated IL-1β release in mice.
Integrative multiomics enhancer activity profiling identifies therapeutic vulnerabilities in cholangiocarcinoma of different etiologies
Authors: Jing Han Hong, Chern Han Yong, Hong Lee Heng, Jason Yongsheng Chan, Mai Chan Lau, Jianfeng Chen, Jing Yi Lee, Abner Herbert Lim, Zhimei Li, Peiyong Guan, Pek Lim Chu, Arnoud Boot, Sheng Rong Ng, Xiaosai Yao, Felicia Yu Ting Wee, Jeffrey Chun Tatt Lim, Wei Liu, Peili Wang, Rong Xiao, Xian Zeng, Yichen Sun, Joanna Koh, Xiu Yi Kwek, Cedric Chuan Young Ng, Poramate Klanrit, Yaojun Zhang, Jiaming Lai, David Wai Meng Tai, Chawalit Pairojkul, Simona Dima, Irinel Popescu, Sen-Yung Hsieh, Ming-Chin Yu, Joe Yeong, Sarinya Kongpetch, Apinya Jusakul, Watcharin Loilome, Patrick Tan, Jing Tan, Bin Tean Teh
Journal: Gut (2023)

Objectives Cholangiocarcinoma (CCA) is a heterogeneous malignancy with high mortality and dismal prognosis, and an urgent clinical need for new therapies. Knowledge of the CCA epigenome is largely limited to aberrant DNA methylation. Dysregulation of enhancer activities has been identified to affect carcinogenesis and leveraged for new therapies but is uninvestigated in CCA. Our aim is to identify potential therapeutic targets in different subtypes of CCA through enhancer profiling. Design Integrative multiomics enhancer activity profiling of diverse CCA was performed. A panel of diverse CCA cell lines, patient-derived and cell line-derived xenografts were used to study identified enriched pathways and vulnerabilities. NanoString, multiplex immunohistochemistry staining and single-cell spatial transcriptomics were used to explore the immunogenicity of diverse CCA. Results We identified three distinct groups, associated with different etiologies and unique pathways. Drug inhibitors of identified pathways reduced tumour growth in in vitro and in vivo models. The first group (ESTRO), with mostly fluke-positive CCAs, displayed activation in estrogen signalling and were sensitive to MTOR inhibitors. Another group (OXPHO), with mostly BAP1 and IDH -mutant CCAs, displayed activated oxidative phosphorylation pathways, and were sensitive to oxidative phosphorylation inhibitors. Immune-related pathways were activated in the final group (IMMUN), made up of an immunogenic CCA subtype and CCA with aristolochic acid (AA) mutational signatures. Intratumour differences in AA mutation load were correlated to intratumour variation of different immune cell populations. Conclusion Our study elucidates the mechanisms underlying enhancer dysregulation and deepens understanding of different tumourigenesis processes in distinct CCA subtypes, with potential significant therapeutics and clinical benefits.
Disentangling the identity of the zona incerta: a review of the known connections and latest implications
Authors: Giulia Arena, Fabrizio Londei, Francesco Ceccarelli, Lorenzo Ferrucci, Elena Borra, Aldo Genovesio
Journal: Ageing Research Reviews (2023)

The zona incerta (ZI) is a subthalamic region composed by loosely packed neurochemically mixed neurons, juxtaposed to the main ascending and descending bundles. The extreme neurochemical diversity that characterizes this area, together with the diffuseness of its connections with the entire neuraxis and its hard-to-reach positioning in the brain caused the ZI to keep its halo of mystery for over a century. However, in the last decades, a rich albeit fragmentary body of knowledge regarding both the incertal anatomical connections and functional implications has been built mostly based on rodent studies and its lack of cohesion makes difficult to depict an integrated, exhaustive picture regarding the ZI and its roles. This review aims to provide a unified resource that summarizes the current knowledge regarding the anatomical profile of interactions of the ZI in rodents and non-human primates and the functional significance of its connections, highlighting the aspects still unbeknown to research.
Coronary microvascular obstruction and dysfunction in patients with acute myocardial infarction
Authors: Mattia Galli, Giampaolo Niccoli, Gianluigi De Maria, Salvatore Brugaletta, Rocco A. Montone, Rocco Vergallo, Stefano Benenati, Giulia Magnani, Domenico D’Amario, Italo Porto, Francesco Burzotta, Antonio Abbate, Dominick J. Angiolillo, Filippo Crea
Journal: Nature Reviews Cardiology (2023)
Correction:<i>Mucus barrier, mucins and gut microbiota: the expected slimy partners?</i>
Journal: Gut (2023)

There is a misspelling of the Cftr gene in this article.The article has Ctfr instead of Cftr in the following sentence, which should read as:For example, during high-fat diet feeding, there is an impairment in mucus production and secretion, an enrichment in barrier-disrupting species, and a decrease in the expression of the Cftr gene in mouse ileal enterocytes, causing a reduction in viscosity and density of the mucus and an increase in intestinal permeability.